tbuckley/cabot-search huggingface dataset:
Abstract 3801: Identification of circular RNAs associated with the ferroptosis of pancreatic cancer cells
Authors: Jessica Jazmin Pena Paladines, Shao Weng Wang, Chi Hin Wong, Yang Chao Chen
Journal: Cancer Research (2023)

Abstract The five-year survival rate for pancreatic cancer patients is significantly low which is predominately due to the lack of early-detection biomarkers, and poor response to currently available treatments that include drug resistance development. Recent studies suggest cancer cells can be highly sensitive to a newly defined type of cell death, ferroptosis, which is related to the development of resistance to standard chemotherapy drugs for pancreatic cancer such as gemcitabine and 5-Fluorouracil. However, the role of circular RNAs (circRNAs) in ferroptosis remains largely unexplored. Hence, this project aims to identify circRNAs in ferroptosis to uncover further components and mechanisms, and potentially provide specific effective targets for anticancer therapies. To achieve this, different ferroptosis inducers were tested, where the cystine-depletion method demonstrated higher efficiency based on cell viability and ferroptosis markers such as iron and lipid peroxidation levels. This method was used to induce ferroptosis for 24 hours in pancreatic cancer cells for subsequent circRNA sequencing, and to establish a ferroptosis-resistant cell line. From the sequencing data, 31 differentially expressed (DE) circRNAs were obtained, and eight were selected for further validation. Three circRNAs; circPPP2R2B, circNDUFAB1, and circNLN, showed consistent differential expression in ferroptosis non-resistant (downregulated) and resistant (upregulated) cells after cystine-depletion treatment. The knockdown of these circRNAs decreased the viability, invasion, migration, and colony formation ability of PDAC cells. Simultaneously, lipid peroxidation and intracellular iron levels, which are ferroptosis markers, were increased. Additionally, bioinformatic analysis of these circRNAs demonstrated their possible interaction with proteins and miRNAs with reported ferroptosis-related functions. In summary, these findings suggest that circPPP2R2B, circNDUFAB1, and circNLN may be critically involved in PDAC progression and the evasion of ferroptosis which supports the further investigation of their oncogenic and ferroptosis-related action mechanism to propose a potential target for anticancer therapies. Citation Format: Jessica Jazmin Pena Paladines, Shao Weng Wang, Chi Hin Wong, Yang Chao Chen. Identification of circular RNAs associated with the ferroptosis of pancreatic cancer cells. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3801.
Abstract 1483: Development of FUBP1 inhibitors to reprogram pancreatic cancer cells into an anti-cancer phenotype
Authors: Alexandra Bunea, Christopher Polera, Aiste Dobrovolskaite, Holly Moots, Otto Phanstiel
Journal: Cancer Research (2023)

Abstract The purpose of this project was to identify small molecules which reprogram tumor cells into an anticancer phenotype. Far upstream binding protein 1 (FUBP1) has been identified as a master regulator of a panel of genes involved in tumor survival including c-Myc and p21. FUBP1 controls gene expression by binding to specific far upstream element (FUSE) DNA sequences of the promoters of key tumor survival genes to regulate their transcription to provide a pro-tumor phenotype (high c-Myc, low p21). This makes FUBP1 a novel therapeutic target as its inhibition reprograms tumors to an anti-cancer phenotype (low c-Myc, high p21). This report describes the development of novel anthranilic acid derivatives which bind to FUBP1 (as shown by ChIP and gel shift assays) and modulate the mRNA and protein expression (qRT-PCR and Western) of FUSE-controlled genes (e.g., c-Myc and p21). The lead compound UCF699 was shown to reprogram pancreatic ductal adenocarcinoma (PDAC) cells into an anti-cancer phenotype in a dose-dependent manner and inhibit pancreatic cancer cell growth. In summary, the ability of UCF699 to control the expression of multiple FUSE-controlled genes and to reprogram tumor cells into an anti-cancer phenotype provides an exciting new way to treat pancreatic tumors. Citation Format: Alexandra Bunea, Christopher Polera, Aiste Dobrovolskaite, Holly Moots, Otto Phanstiel. Development of FUBP1 inhibitors to reprogram pancreatic cancer cells into an anti-cancer phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1483.
Abstract 522: Selective estrogen receptor a-UPR activators (SERA): a novel class of small molecules that eradicate estrogen receptor positive tumors
Authors: Michael P. Mulligan, Matthew W. Boudreau, David J. Shapiro, Timothy M. Fan, Paul J. Hergenrother, Kerry Barnhart, David Azorsa, Jeff Kiefer, Spyro Mousses
Journal: Cancer Research (2023)

Abstract While therapy of estrogen receptor alpha positive (ERα+) breast cancer is often initially successful with ERα modulating or inhibiting drugs, eventual drug resistance is universal and such treatments are rarely curative. To address this considerable medical need, several generations of novel anti-tumor small molecule agents specifically targeting the estrogen-ERα interaction have been synthesized and characterized. We are pursuing an alternative approach, activation of an endogenous cell death pathway downstream of ERα with non-competitive Selective Estrogen Receptor Activators (SERAs). These compounds exhibit their effects by dysregulating calcium homeostasis in ERα+ tumor cells leading to hyper-activation of the anticipatory unfolded protein response (a-UPR) and necrotic cell death, a mechanism distinct from current breast cancer therapeutics. These molecules cause increases in P-EIF2a and P-AMPK, and cleavage of ATF6α, which are all hallmarks of the hyper-activation of a-UPR. SERA molecules cause death of ERα+ breast cancer cells in culture with 24hr IC50 values in the low nanomolar range, including breast cancer cell lines harboring ERα mutations known to contribute to acquired ERα modulator therapy resistance, while IC50 values in ERα-negative cells are orders of magnitude higher. In the MCF-7 ERα+ breast cancer xenograft model, once weekly IV injections of SERA2 at 10mg/kg cause durable, complete tumor regression, and SERA2 also has impressive activity in a challenging-to-treat PDX model that is resistant to fulvestrant and tamoxifen. SERAs are well-tolerated after multiple intravenous injections in mice, rats, and dogs, and clinical trial-compatible formulations have been developed. These findings suggest that SERA molecules can address the important unmet clinical need for more effective therapies for patients with ERα+ tumors who progress on conventional SERM, SERD, and targeted therapies. Citation Format: Michael P. Mulligan, Matthew W. Boudreau, David J. Shapiro, Timothy M. Fan, Paul J. Hergenrother, Kerry Barnhart, David Azorsa, Jeff Kiefer, Spyro Mousses. Selective estrogen receptor a-UPR activators (SERA): a novel class of small molecules that eradicate estrogen receptor positive tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 522.
Abstract 5365: Extracting novel knowledge from scientific literature to build a web portal for cancer researchers to keep up with the latest scientific discoveries
Authors: Feng Pan, Yuan Zhang, Xin Sui, Donghu Sun, Menghan Chung, Jinfeng Zhang
Journal: Cancer Research (2023)

Abstract Millions of new papers are published in biomedical sciences every year. In many disciplines, it has become impossible to read all the published new papers to learn what is happening in the frontier of a particular area. This gap is widening as the publishing speed has been accelerating in recent years. To address this challenge, one can convert unstructured text data into a structured form, which can then support highly accurate information retrieval, information integration, and automated knowledge discovery. A plausible approach for such a task is to use named entity recognition (NER) and relation extraction (RE) methods to identify important biological entities and extract their relations to construct knowledge graphs (KGs). The LitCoin Natural Language Processing (NLP) Challenge was recently organized by NCATS of NIH and NASA to spur innovation by rewarding the most creative and high-impact uses of biomedical text to create KGs. In addition to entities and relations, the manually annotated LitCoin dataset also contains the annotations of relations being new discoveries or background knowledge. Our team participated in the challenge and ranked first place. The novelty prediction model of our pipeline has achieved an F1 score of 0.90. We have applied our model to all the PubMed abstracts published previously and the newly published ones to extract the novel discoveries in each article. A web portal has been created to allow scientists to view the latest discoveries in cancer research. The web portal is updated daily with versatile visualization tools for cancer researchers to quickly grasp the latest discoveries in a particular area. It also offers powerful functions to explore the existing literature and make sophisticated inferences about causal and indirect relationships. Citation Format: Feng Pan, Yuan Zhang, Xin Sui, Donghu Sun, Menghan Chung, Jinfeng Zhang. Extracting novel knowledge from scientific literature to build a web portal for cancer researchers to keep up with the latest scientific discoveries. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5365.
Abstract 1476: FOXM1 inhibition: A novel therapeutic approach for small cell lung cancer
Authors: Md Arafat Khan, Parvez Khan, Mahek Fatima, Asad Ur Rehman, Shailendra Kumar Maurya, Sameer Mohiuddin, Ramakanth Chirravuri Venkata, Jesse L. Cox, Sung Hoon Kim, Benita S. Katzenellenbogen, John A. Katzenellenbogen, Apar K. Ganti, Surinder K. Batra, Mohd Wasim Nasser
Journal: Cancer Research (2023)

Abstract Outcomes from small cell lung cancer (SCLC) are dismal. Most SCLC patients have distant metastasis at diagnosis and the 5-year survival of these patients is around 2.8%. Despite initial response to chemotherapy and immunotherapy, relapses are very common. No targeted therapy is available for SCLC. Thus, there is an urgent need to understand the acquisition of chemoresistance, and to identify novel targets and therapeutic strategies for this deadly disease. Recently, FOXM1 was identified as an essential component in SCLC tumor growth. Our aim is to develop FOXM1-targeted therapy to thwart SCLC progression and the development of chemoresistance. We have targeted FOXM1 using highly specific small molecule inhibitor FDI-6 and found that FOXM1 inhibition drastically reduces colony formation and cell migratory capabilities in multiple SCLC cell lines (SBC3, SBC5). Additionally, we observed that FOXM1 downregulation via FDI-6 reduced SCLC growth both as monotherapy and in combination with cisplatin. Based on these studies, we conclude that FOXM1 inhibition alone or in combination with cisplatin could be a unique therapeutic approach for SCLC. Citation Format: Md Arafat Khan, Parvez Khan, Mahek Fatima, Asad Ur Rehman, Shailendra Kumar Maurya, Sameer Mohiuddin, Ramakanth Chirravuri Venkata, Jesse L. Cox, Sung Hoon Kim, Benita S. Katzenellenbogen, John A. Katzenellenbogen, Apar K. Ganti, Surinder K. Batra, Mohd Wasim Nasser. FOXM1 inhibition: A novel therapeutic approach for small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1476.
Abstract 6307: A novel pegylated bispecific antibody-drug conjugate (P-BsADCpb-adc) targeting cancers co-expressing PD-L1 and CD47
Authors: Shumin Liu, Weidong Lyu, Shuqiang Yin, Yang Lei, Qiudong Zhuo, Liling Zheng, Bin Sun, Shuangyu Tan, Lidong Jiang, Teng Zhang, Bo Gao, Rui Xu, Dechang Huang, Yong Li, Zibin Wu, David Wu, Yvonne (Yu) Wen
Journal: Cancer Research (2023)

Abstract ADCs have demonstrated improved efficacy and target selectivity comparing to the non-specific small molecule cytotoxicity drugs in cancer treatment. Yet, in solid tumor therapies, effort for further improvement of efficacy and safety has been hindered by the poor tumor penetration of conventional IgG based ADC, low internalization efficiency, undesired efflux of ADC from tumor cells, narrow therapeutic window due to the on-target/off tumor and Fc induced toxicity, etc. To address those issues, we previously reported that the compound JY201, a Polyethylene Glycol (PEG)-based bispecific ADC (P-BsADC) targeting two epitopes of Her2, demonstrated advantages in tumor penetration, internalization efficiency, lysosome trafficking, no Fc related toxicity, and better efficacy in tumor inhibition than transtuzumab deruxtecan (Ds-8201). In this study, we reveal another novel pegylated P-BsADC (JY207) formed by site-specific conjugation of a bispecific single chain fusion protein targeting PD-L1 and CD47 with PEG-MMAE (a pegylated cytotoxic payload MMAE). As expected, the compound JY207 retains all the advantages that JY201 possesses. Furthermore, JY207 does not bind to human red blood cells, but preferentially binds to CD47/PD-L1 double positive tumor cells, thus reduces the possibility of on-target toxicities. In vitro cytotoxicity studies showed that JY207 has strong potencies in CD47/PD-L1 double positive tumor cells, while showing almost no killing effect to CD47 or PD-L1 single positive tumor cells. In CDX models and a PDX model of transplanted tumor tissues from lung cancer patients, the compound demonstrated excellent tumor inhibition at low doses. In an in vitro plasma stability test, JY207 displays high stability in cynomolgus monkey and human serums. Preliminary repeated-dosing toxicological study has found the maximum tolerated dose of JY207 in CD47/PD-L1 double transgenic mice is 50mg/kg. In vivo pharmacokinetics and toxicological studies of JY207 are being conducted in cynomolgus monkeys and are expected to show desirable results. All those findings in this study warrant JY207 as a promising candidate for the clinical development for patients with CD47/PD-L1 double positive cancers. Citation Format: Shumin Liu, Weidong Lyu, Shuqiang Yin, Yang Lei, Qiudong Zhuo, Liling Zheng, Bin Sun, Shuangyu Tan, Lidong Jiang, Teng Zhang, Bo Gao, Rui Xu, Dechang Huang, Yong Li, Zibin Wu, David Wu, Yvonne (Yu) Wen. A novel pegylated bispecific antibody-drug conjugate (P-BsADCpb-adc) targeting cancers co-expressing PD-L1 and CD47. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6307.
Abstract 3799: Regulation of p16-E2F1-CDK4/6 signaling by TRUC-16 ultraconserved long non-coding RNA
Authors: Linda Fabris, Erik Knutsen, Maria Teresa S. Bertilaccio, Steliana Calin, Recep Bayraktar, George T. Eisenhoffer, Leonard Girnita, George A. Calin
Journal: Cancer Research (2023)

Abstract High phylogenetic conservation of genomic loci is a potential marker of essential biological functionality. Ultraconserved elements (UCEs) are DNA sequences entirely conserved through millions of years of evolution, but their functions are not well understood. Several long non-coding RNAs (lncRNAs) are transcribed from UCEs and play active roles in cancer development. Using a combination of in vitro and in vivo experiments with two animal models and 4 patient cohorts, we discovered several remarkable aspects of ultraconservation. Using a multi-step genetically defined carcinogenesis model, we identified one UCE, uc.206, and its associated overexpressed lncRNA TRUC-16 as a regulator of cell proliferation in chronic lymphocytic leukemia (CLL). High levels of TRUC-16 inhibit p16INK4A translation, causing increased proliferation through an E2F1-mediated mechanism in CLL patients, as well as in zebrafish and murine models. uc.206/TRUC-16 function is extremely conserved throughout evolution. We found cell cycle-related effects of TRUC-16 in both mice and zebrafish, in which we observed increased proliferation of blood cells after overexpression of the human TRUC-16. High levels of CDK4/6 consequent to TRUC-16 overexpression and p16 decrease can be specifically targeted in both CLL and Richter’s Transformation (RT), a rare but deadly consequence of CLL. Inhibition of CDK6 is a therapeutic option never tested in CLL, but in use for another type of B cell malignancy, such as the mantle cell lymphoma. Our results highlight the multifaceted contribution of a UCE to human tumorigenesis and open new possibilities for the use of long-noncoding RNAs in cancer therapies. Citation Format: Linda Fabris, Erik Knutsen, Maria Teresa S. Bertilaccio, Steliana Calin, Recep Bayraktar, George T. Eisenhoffer, Leonard Girnita, George A. Calin. Regulation of p16-E2F1-CDK4/6 signaling by TRUC-16 ultraconserved long non-coding RNA. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3799.
Abstract 6301: Post-translational modifications regulate sensitivity to Polatuzumab Vedotin in DLBCL
Authors: Sean R. Corcoran, Louis M. Staudt, Daniel Hodson
Journal: Cancer Research (2023)

Abstract Diffuse Large B-Cell Lymphoma (DLBCL) is an aggressive malignancy of which one-third of diagnosed patients ultimately relapse and die. New treatment paradigms for relapsed-refractory patients are needed. Most DLBCL tumors are reliant on signaling through their cell surface B-cell receptor (BCR) mediated by ITAMs on CD79A and CD79B to drive anti-apoptotic NF-kB and PI3 kinase signaling. In order to understand how surface BCR is regulated, we performed whole genome CRISPR screens in 9 DLBCL cell lines in which we sorted for high and low surface CD79B or added the CD79B targeted antibody-drug conjugate Polatuzumab-Vedotin (POLA-V). Strikingly, independent of genetic or cell of origin subtype, sgRNAs encoding the entire N-linked glycosylation pathway and specific sugar modification by addition of galactose and sialic acid were found to be enriched in high CD79B fractions and depleted in POLA-V treated samples compared to control. Further testing showed that removing sialic acid by treating with a small molecule inhibitor of sialic acid, genetic perturbation of golgi sugar transporters SLC35A1 and SLC35A2, or the a2,6 sialyltransferase ST6GAL1 resulted in more surface CD79B antibody binding with no significant change in CD79B protein abundance. The specificity of the effect of sialic acid loss on POLA antibody binding was confirmed by removing cell surface sialic acid with exogenous sialidase and observing increased binding of POLA, but not other therapeutic antibodies like Rituximab or CD19 FMC-63. Loss of SLC35A1, SLC35A2, and ST6GAL1 synergized with POLA-V but not the drug conjugate MMAE alone, showing a BCR dependent mechanism of sialic acid loss on POLA-V sensitization. In a further cell of origin subtype analysis of the germinal center B-cell (GCB) DLBCL cell lines, loss of the E3 ligase KLHL6 was found to synergize with POLA-V. Importantly, KLHL6 is heavily mutated across all germinal center derived malignancies, is more highly expressed in germinal center B-cells than other members of the B-cell lineage, and plays an unknown role in the development of autoimmune diseases. Further work will give evidence for the target of KLHL6 mediated ubiquitination and will show how this gene can drive lymphoma and autoimmune disease development in the germinal center. Citation Format: Sean R. Corcoran, Louis M. Staudt, Daniel Hodson. Post-translational modifications regulate sensitivity to Polatuzumab Vedotin in DLBCL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6301.
Abstract 6454: Metabolic obesity phenotype and risk of obesity-related cancers in the women's health initiative
Authors: Prasoona Karra, Maci Winn, Garnet Anderson, Benjamin Haaland, Aladdin H. Shadyab, Marian Neuhouser, Rebecca Seguin-Fowler, Cynthia A. Thomson, Mace Coday, Jean Wactawski-Wende, Marcia L. Stefanick, Xiaochen Zhang, Ting-Yuan David Cheng, Shama Karanth, Yangbo Sun, Nazmus Saquib, Margaret Pichado, Su Yon Jung, Fred Tabung, Scott A. Summers, William L. Holland, Thunder Jalili, Marc Gunter, Sheetal Hardikar, Mary C. Playdon
Journal: Cancer Research (2023)

Abstract Introduction: Body mass index (BMI) may misclassify obesity-related cancer (ORC) risk since metabolic dysfunction can exist at any BMI. We measured the association of metabolic dysfunction, independent of BMI with risk of ORC. Methods: Study included 60% white and 34% black Women’s Health Initiative participants with available baseline cardiovascular disease biomarkers. Metabolic obesity phenotypes were classified as normal weight with no metabolic dysfunction (NWNMD), normal weight with metabolic dysfunction (NWMD), overweight/obese with no metabolic dysfunction (OONMD) and overweight/obese with metabolic dysfunction (OOMD) when defined by Wildman and ATP III criteria. We performed a Cox proportional hazards regression with death as a competing risk adjusting for confounders. Results: Defining by Wildman and ATP III criteria, 17.0%, 6.5%, 31.0%, 45.0%; and 22.2%, 2.4%, 41% and 35% were NWNMD, NWMD, OONMD and OOMD respectively. The risk of all ORC combined was elevated among NWMD (HR 1.12, 95% CI: 0.90-1.39), OONMD (HR 1.15, 95% CI: 1.00-1.32) and OOMD (HR 1.35, 95% CI: 1.18-1.54) when compared to NWNMD using Wildman criteria. Results were similar when defined by ATP III, hs-CRP and HOMA-IR. When stratified by cancer type, NWMD were at increased risk of colorectal cancer when compared to NWNMD (HR 1.70, 95% CI: 1.02-2.82). Individuals who were overweight/obese were at increased risk of cancer for all cancer types though the effect estimates were lower among OONMD phenotype. Conclusions: NWMD and OOMD individuals are at increased risk of all ORC combined, independent of BMI status when compared to individuals with NWNMD. Citation Format: Prasoona Karra, Maci Winn, Garnet Anderson, Benjamin Haaland, Aladdin H. Shadyab, Marian Neuhouser, Rebecca Seguin-Fowler, Cynthia A. Thomson, Mace Coday, Jean Wactawski-Wende, Marcia L. Stefanick, Xiaochen Zhang, Ting-Yuan David Cheng, Shama Karanth, Yangbo Sun, Nazmus Saquib, Margaret Pichado, Su Yon Jung, Fred Tabung, Scott A. Summers, William L. Holland, Thunder Jalili, Marc Gunter, Sheetal Hardikar, Mary C. Playdon. Metabolic obesity phenotype and risk of obesity-related cancers in the women's health initiative [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6454.